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Differential Expression of Metallothionein in Gastrointestinal Stromal Tumors and Gastric Carcinomas.

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THE ANATOMICAL RECORD 294:267–272 (2011)
Differential Expression of
Metallothionein in Gastrointestinal
Stromal Tumors and Gastric Carcinomas
ELIZA TING-LI SOO,1 CHENG-TENG NG,1 GEORGE WAI-CHEONG YIP,1
CHUAY YENG KOO,1 MIN-EN NGA,2 PUAY-HOON TAN,3 AND BOON-HUAT BAY1*
1
Department of Anatomy, National University of Singapore, Singapore
2
Department of Pathology, National University of Singapore, Singapore
3
Department of Pathology, Singapore General Hospital, Singapore
ABSTRACT
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors
that account for about 2% of gastric tumors. Metallothioneins (MTs) are
multifunctional proteins associated with carcinogenesis and known to be
coded by 10 functional MT genes. This study evaluated MT mRNA and protein expression in GISTs and compared the expression levels with gastric
carcinomas. An immunohistochemical study of MT protein expression was
performed in 15 GISTs (specifically located in the stomach) and 38 early
stage gastric carcinomas. The percentage of cells stained and intensity of
staining were determined. MT-2A mRNA expression was investigated in 6
GISTs and 6 early stage gastric carcinoma patients. All GISTs displayed
positive nuclear immunostaining, with most GISTs having predominantly
mildly stained nuclei (93.3%). On the other hand, 37 out of 38 gastric carcinoma cases were positively stained for nuclear MT with 24 cases (63.2%)
exhibiting predominantly mild nuclear staining, 7 cases (18.4%) moderate
nuclear staining, and 6 cases (15.8%) strong nuclear staining. Nuclear MT
expression was found to be significantly lower in GIST samples when compared with gastric carcinoma tissues based on the percentage stained and
immunoreactive score. We then established that the MT-2A gene transcript
was the most abundant MT isoform in MKN28 gastric cancer cells and analyzed its expression in GIST and gastric carcinoma tissues. We found that
GISTs had significantly lower MT-2A mRNA levels than gastric carcinoma
tissues. Lower MT-2A gene expression and nuclear MT protein expression
in GISTs when compared with gastric carcinomas may reflect their different underlying biology and divergent histogenesis. Anat Rec, 294:267–272,
C 2010 Wiley-Liss, Inc.
2011. V
Key words: metallothionein; MT-2A;
GIST; gastric carcinoma
Gastrointestinal stromal tumors (GISTs) are specific
mesenchymal tumors that account for about 2% of gastric tumors and reported to be most common in the
stomach (60–70%) followed by the small intestine (25–
35%) (Miettinen et al., 1998). Other examples of submucosal mesenchymal tumors of the gastrointestinal tract
include leiomyosarcomas and gastrointestinal Kaposi’s
sarcoma (Ponsaing et al., 2007). GISTs occur mainly in
middle-aged and older people and are rarely found in
patients below the age of 40 (Miettinen et al., 1999a). It
C 2010 WILEY-LISS, INC.
V
immunohistochemistry;
Grant sponsor: National Research Foundation, Singapore;
Grant number: NMRC/TCR/001/NUS/2007.
*Correspondence to: Boon-Huat Bay, Department of Anatomy,
Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Blk MD10, S117 597, Singapore. Fax:
þ65-6778 7643. E-mail: bay_boon_huat@nuhs.edu.sg
Received 16 July 2010; Accepted 7 November 2010
DOI 10.1002/ar.21321
Published online 23 December 2010 in Wiley Online Library
(wileyonlinelibrary.com).
268
SOO ET AL.
has been reported that as a significant number of GISTs
are less than 2 cm and asymptomatic, these tumors are
detected only incidentally during surgery for unrelated
diseases (Miettinen et al., 1999a).
GISTs comprise several distinct morphologic patterns
including epithelioid, spindle cell, mixed and occasionally
pleomorphic types (Miettinen and Lasota, 2006). The
most specific diagnostic criterion to date for GIST is detection of c-KIT expression immunohistochemically (Hirota
et al., 1998; Sarlomo-Rikala et al., 1998; Liegl-Atzwanger
et al., 2010). C-KIT protein (CD117) expression has been
reported to be 95% positive in GIST and suggested by the
World Health Organization to be a defining feature of
GISTs (Ponsaing et al., 2007). Gene mutation of KIT or
platelet-derived growth factor receptor alpha are reported
to induce oncogenic signalling in the absence of their
ligands, leading to activation of the PI3K-AKT and MEKMAPK pathways that promote tumorigenesis (Heinrich
et al., 2003; Rossi et al., 2006; Liegl-Atzwanger et al.,
2010). Most GISTs are positive for CD34 and heavy
molecular weight caldesmon (Miettinen et al., 1999b;
Miettinen et al., 2006). GISTs are also typically negative
for S100-protein and rarely express desmin—an intermediate filament protein (Miettinen et al., 2000).
Gastric carcinoma, an epithelial cancer, is the fourth
most common cancer worldwide. It is the second cause of
cancer mortality leading to 700,000 deaths annually
(Parkin et al., 2005). The incidence of gastric carcinoma is
reported to be highest in Asian countries, though timetrend studies have shown a decrease incidence of this
cancer in many countries in Asia (Fock and Ang, 2010).
Gastric carcinoma is a genetically heterogeneous disease
associated with multiple carcinogenic pathways (Panani,
2008). In fact, the occurrence of gastric carcinoma in Asian
population tends to mirror the seroprevalence rate of Helicobacter pylori infection although this is not always seen
(Fock and Ang, 2010). Even though early gastric carcinomas have a favourable clinical outcome, advanced (unresectable or recurrent) cases have a poor prognosis,
resulting in the call for new approaches to therapy such as
a biomarker oriented strategy (Boku, 2010). One biomarker investigated is metallothionein (MT), which is
known to be expressed in a cell-specific and tissue-specific
manner in different types of tumors (Cherian et al., 2003).
MTs are low molecular metal-binding proteins first
discovered in 1957 by Margoshes and Vallee (Margoshes
and Vallee, 1957; Klaassen et al., 1999). There are at
least 10 functional MT genes (MT-1A, 1B. 1E, 1F, 1G,
1H, 1X, 2A, 3, and 4 isoforms) encoding four MT proteins. As MTs are multifunctional proteins, they have
been implicated in carcinogenesis and tumor progression
in a variety of cancers (Coyle et al., 2002; Cherian et al.,
2003; Thirumoorthy et al., 2007). In this study, we
evaluated the expression of MT in GISTs and gastric
carcinoma by immunohistochemical staining and realtime quantitative real-time polymerase chain reaction
(RT-PCR) to investigate if there is differential expression
of MT in tumors arising from histological layers of the
stomach with different embryonic origins.
MATERIALS AND METHODS
Patients and Tumor Samples
A total of 15 GISTs with specific location in the stomach and 38 early stage (Stage 1 and 2) gastric carcinoma
cases were included in the study. These tissue samples
were obtained from patients who had undergone surgery
at the National University Hospital (NUH), and the use
of tissues for research was approved by the Institutional
Review Board. The histological diagnosis was made on
haematoxylin and eosin (H&E) stained slides according
to standard criteria. The tissues were fixed in 10%
formalin and embedded in paraffin for immunohistochemical studies. Immunostaining results of a panel of
markers, viz., CD 117, CD34, S-100, desmin, and proliferating cell nuclear antigen (PCNA), were retrieved
from the pathological data sheets of the GISTs. For
gastric cancer, there were 26 intestinal type, 9 diffuse
type, and 3 mixed type as categorized by the Lauren
classification. All the samples were harvested by pathologists from the Department of Pathology, NUH.
Immunohistochemistry
Immunohistochemistry on paraffin-embedded GISTs
and gastric carcinomas performed using the Leica
BondTM-Max System (Leica Microsystems, Wetzlar,
Germany) with fully automated immunohistochemical
staining. The primary MT antibody (Dako Corporation,
Carpinteria, CA) was diluted by 100 times. The time for
each run was 2 hr and 30 min. A drop of Permount
mounting medium (Fisher-Scientific, Fair Lawn, NJ)
was applied to each slide and mounted with a coverslip.
Stained slides were scanned using ScanScope digital
scanners (Aperio, Vista, CA). The scanned slides were
then viewed and scored using the Aperio ImageScope to
determine the intensity of immunostaining. MT immunopositivity was defined as the presence of cytoplasmic and/or
nuclear staining. The intensity of staining was scored as
0 (no detectable immunoreactivity), 1þ (mild staining), 2þ
(moderate staining), and 3þ (strong staining). The following
methods were used to quantitate nuclear staining: percentage stained and immunoreactive score (IRS). IRS was
derived from the sum of all the products of each stained intensity with the corresponding percentage stained.
Cell Culture
Moderately differentiated human MKN28 gastric cancer cells (a gift from Professor Y. Ito, National Cancer
Institute Singapore) were cultured in Roswell Park
Memorial Institute medium (RPMI 1640) (Gibco, Grand
Island, NY) supplemented with 10% heat-inactivated
fetal bovine serum (FBS) (Hyclone, Logan, UT) and 100
units/mL penicillin and 100 lg/mL streptomycin (Invitrogen, Carlsbad, CA) and maintained at 37 C in a 5%
CO2 incubator.
Immunocytochemistry
A total of 5 104 MKN28 cells were seeded separately
into Lab-TekTM 4-well chamber coverglass (Nalge Nunc
International, Rochester, NY). Cells were fixed with 4%
paraformaldehyde. Primary mouse anti-horse antibody
E9 ((Dako) at a dilution factor of 1:200 was added and
incubated at 4 C, overnight. A negative control (without
the addition of MT antibody) was included. Biotinylated,
affinity-purified secondary anti-mouse antibody at the
same dilution factor was added for 1 hr at room temperature. The cells were washed, incubated for 1 hr at room
269
MT EXPRESSION IN GISTS AND GASTRIC CANCER
temperature with ABC solution (Avidin DH and Biotinylated Horseradish Peroxidase H diluted in PBS-TX)
(Vector Laboratories, Burlingame, CA) followed by the
addition of 3,3-diaminobenzidene (DAB) mixture (including TBS and hydrogen peroxide) for 10 min. The cells
were counterstained with Shandon’s Haematoxylin,
rinsed in distilled water, dehydrated using alcohol and
histoclear to remove alcohol. The glass cover slip was
mounted onto a glass slide with Permount mounting
medium and air dried.
Quantitative RT-PCR
RNA was reversed transcribed to cDNA using the
Superscript III system (Invitrogen). For RT-PCR analysis, primers that target the eight functional MT-1 and
MT-2 isoforms were adopted from Mididoddi et al.
(1996). The house-keeping gene glyceraldehyde-3-phosphate-dehydrogenase (G3PDH) was included as a normalization control. The primers used for G3PDH were:
forward 50 -GAA GGT GAA GGT CGG AGT CAA CG-30 ;
reverse 50 -TGC CAT GGG TGG AAT CAT ATT GG -30 .
The following RT-PCR conditions were used: 95 C for 15
min for denaturation, followed by 50 cycles of 94 C for
15 sec, 55 C for 40 sec and 72 C for 20 sec for annealing.
The fluorescence from SYBR Green was determined at
the melting temperature of 50–60 C, 20 sec followed by
cooling at 72 C, 30 sec. Quantification was calculated
using DCT, which is the difference between the target
gene and G3PDH. The specificity of PCR products was
further verified by agarose gel electrophoresis of the
resulting PCR products.
TissueScan Array
GISTs and gastric carcinoma (1 Stage IA, 2 Stage IB,
and 3 Stage II) tissues were selected from the TissueScan Gastroesophageal Tissue qPCR Panel I (OriGene,
Rockville, MD). Each plate was removed from a 20 C
refrigerator and allowed to warm to room temperature.
A pre-mix was prepared and aliquoted into each of the
48 wells according to the manufacturer’s protocol. The
plate was then covered with a new adhesive cover sheet
and sealed tightly by pressing the cover around each
well before placing on ice for 15 min to allow the cDNA
to dissolve. SYBR Green dye was used as the reporter
dye in this experiment. The specific MT-2A primers used
were forward 50 -GGA TCC GAT CCC AAC TGC TCC
TGC GCC-30 ; reverse 50 -CTC GAG TCA GGC GCA GCA
GCT GCA CTT-30 . RT fluorescent detection of PCR products was performed using Applied Biosystems 7500
Real-Time PCR System (Applied Biosystems, Carlsbad,
CA) with the following thermocycling conditions: 95 C
for 15 min for one cycle, followed by 40 cycles of 94 C for
15 sec, 60 C for 30 sec, and 72 C for 60 sec. The CT
values were obtained for further analysis.
TABLE 1. Immunohistochemical staining of MT
and a panel of markers specific for GIST
S/No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Nuclear
MT (%)
Cyto
MT (%)
CD117
CD34
S100
Desmin
22.5
10
12.5
12.5
50
5
5
35
22.5
5
20
25
5
5
5
17.5
5
0
10
75
5
15
3.5
7.5
0
30
10
0
2.5
0
N
P
N
N
P
P
P
N
P
P
P
P
P
P
P
P
P
N
P
P
P
P
N
P
P
P
P
P
P
P
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
P
N
RESULTS
Immunohistochemical Staining of MT and
Panel of Biomarkers
Nuclear MT immunopositivity was observed in all the
GIST sections, whereas 11 out of 15 (73.3%) GISTs demonstrated immunostaining in the cytoplasm (Table 1).
The percentage of nuclear MT-immunopositive cells
ranged from 5 to 50%. Most GIST tissue sections (93.3%)
were predominantly mildly stained (Fig. 1B), with only 1
tissue section (6.7%) having moderate staining. The negative control for the immunohistochemical staining is
shown in Fig. 1A. The IRS scores ranged from 5 to 55.
For gastric carcinoma cases, both nuclear and cytoplasmic MT immunopositivity were present in 37 out of 38
(97.4%) tissues. The intensity of immunohistochemical
staining among the MT positive gastric carcinoma tissues was variable. There was no MT immunostaining
observed in 1 tissue section (2.6%), whereas 24 cases
(63.2%) exhibited predominantly mild nuclear staining,
7 cases (18.4%) moderate nuclear staining, and 6 cases
(15.8%) strong nuclear staining (Fig. 1C). Nuclear MT
expression was significantly higher in gastric carcinoma
tissue samples when compared with GIST tissue samples when analyzed by percentage stained and IRS
(Table 2). With regard to cytoplasmic staining, 4 GISTs
(26.7%) had no MT immunostaining and 1 out of the 38
gastric carcinoma cases (2.6%) stained negatively for
MT. There was also variable cytoplasmic MT staining in
GISTs (Table 1) and gastric carcinomas, but no significant difference was found between the two groups.
Among the GISTs, 73.3% were positive for CD117 and
86.7% positive for CD34 with 100% staining negatively
for S-100 and 93.3% for desmin (Table 1). All the GIST
sections were positive for PCNA staining.
Statistical Analysis
Functional MT-1 and MT-2 MT mRNA
Expression in MKN28 Gastric Cancer Cells
The GraphPad Prism 5 (GraphPad Software, USA)
was used for statistical analyses. The Student t-test was
performed for comparison of data between gastric cancer
and GIST. Results with P < 0.05 were considered statistically significant.
MT protein expression was observed in the MKN28
gastric cancer cells (Fig. 2A). As MT has 10 known functional isoforms, an in vitro screening of the expression of
the 7 functional MT-1 and 1 MT-2 genes were analyzed
in gastric cancer cells to determine which MT gene
270
SOO ET AL.
Fig. 1. Immunostaining of MT in GIST and gastric carcinoma tissue
samples. (A) Negative control for MT immunostaining (with the addition of diluent in place of primary antibody) in gastric tissue section.
Magnification 200. (B) GIST section displaying predominantly mild
nuclear MT staining and cytoplasmic staining of tumor cells. Magnification 200. (C) Gastric carcinoma section showing strong MT
nuclear staining (##) with scattered nuclei being moderately immunostained (#). Magnification 400.
TABLE 2. Nuclear MT expression in GIST and
gastric cancer tissue samples
DISCUSSION
Parameters
Nuclear % stained
Mean
SEM
P Value
Nuclear IRS
Mean
SEM
P Value
GIST
(N ¼ 15)
Gastric
Cancer (N ¼ 38)
16.00
3.44
53.68
5.26
<0.0001
21.09
4.13
91.58
10.64
0.0002
should be used for analysis of the GIST and gastric carcinoma tissues. The MT-3 and MT-4 genes were not evaluated as MT-3 is known to be specific for the brain and
MT-4 present in stratified epithelium (Cherian et al.,
2003). The MT-1A, 1B, 1E, 1G, and 1H transcripts were
not detectable in MKN28 gastric cancer cells. As shown
in Fig. 2B, MT-1F, 1X, and 2A isoforms were detectable
in MKN28 cells by RT-PCR with the MT-2A isoform
being the most abundant MT isoform. The specificity of
the MT-1F, 1X, and 2A primers was validated using
melting curve analysis (not shown) and demonstrated as
single band amplicons in 2% agarose gel electrophoresis
after RT-PCR amplification (Fig. 2C).
MT-2A mRNA Expression
The MT-2A gene was selected for further analysis, and
MT-2A mRNA expression was determined in 6 GISTs
and 6 early stage (Stage 1 and Stage 2) gastric carcinomas selected from the TissueScan Gastroesophageal
Tissue qPCR Panel I. The cDNA samples were prenormalized by the manufacturer, and only the MT-2A gene
was probed in this experiment. As shown in Fig. 3, there
was a significant difference in CT values of MT-2A
mRNA obtained from patients with GIST when compared with early stage gastric carcinoma (P ¼ 0.0013).
As higher CT values are correlated with lower MT-2A
gene expression, tissues from patients diagnosed with
GIST had a lower MT-2A mRNA expression compared
with tissues from gastric carcinoma patients.
MTs are known to protect against apoptosis, oxidative
stress, proliferation, angiogenesis, and much research
has been dedicated to explore their role in tumor progression and other related areas (Cherian et al., 2003;
Pedersen et al., 2009). MT has been reported to be overexpressed in several human carcinomas including the
breast, ovary, laryngeal, oral cavity, lung (non-smallcell), skin, uterus, and pancreas, but downregulated in
other cancers such as gastric, colorectal, liver, and central nervous system tumors (Pedersen et al., 2009). In
this study, we observed nuclear expression of MT as
determined by immunohistochemistry in all the GISTs,
which had mainly positive immunoreactivity for CD117
although the percentage was lower than expected (Ponsaing et al., 2007), positive CD34 staining and negative
staining for S-100 protein and desmin. As MTs are
known to affect cell proliferation, there is a possibility
that MT may be involved in proliferation in GISTs, since
PCNA (a proliferative marker) was observed to be immunopositive in all the GIST tissues examined. Some investigators have also argued that nuclear expression of MTs
is related to their ability to protect cells against genotoxicity, giving rise to acquisition of malignant phenotype
(Dutsch-Wicherek et al., 2008; Pedersen et al., 2009).
However, MT expression was considerably lower in
GISTs when compared with early stage gastric carcinoma tissue samples. Interestingly, results from both
methods used for quantitation of the MT-immunostaining, namely, percentage stained and IRS were convergent and showed significantly decreased MT expression
in GISTs. We also found that MT-2A mRNA expression
was significantly downregulated in GISTs compared to
gastric carcinoma samples. With regard to MT staining
in GIST, Perez-Gutierrez et al. (2007) previously compared MT immunohistochemical expression in 92 GIST
and 14 gastrointestinal leiomyosarcomas (GILMS) but
found no significant difference in MT expression. They
also did not find any association between MT expression
and the anatomical location of the GISTs (gastric when
compared with intestinal). GISTs are most commonly
found in the stomach, but cases have also been found in
the small intestines, large bowel, and oesophagus (Miettinen et al., 1998).
MT EXPRESSION IN GISTS AND GASTRIC CANCER
271
Fig. 3. MT-2A mRNA expression in GIST and gastric carcinoma
samples. Lower CT value denotes higher MT-2A expression. The values are expressed as CT values as the cDNAs present in the 48 wells
have been prenormalized by the manufacturer using the housekeeping
gene, b-actin. Values are means of 6 samples for GIST and 6 samples
for gastric carcinoma. Error bar ¼ SD.
Fig. 2. Expression of MT in MKN28 gastric cancer cells in vitro. (A)
Positive MT protein expression in MKN28 cells. Magnification 200.
Bar ¼ 100 lm. (B) MT-1F, 1X, 2A mRNA expression in MKN28 gastric
cancer cells. The housekeeping gene G3PDH was used for normalization. A higher DCT value indicates lower expression. Values are means
of triplicates. Error bar ¼ SEM. (C) Gel electrophoresis of RT-PCR
products of MT-2A and G3PDH. The MT-2A bands (left) and G3PDH
bands (right) visualized were obtained from three different samples.
The reports on MT expression in gastric cancer have
not been consistent. In an immunohistochemical analysis of 112 surgical gastric samples comprising 38 early
gastric carcinomas and 74 advanced cases, Tuccari and
colleagues showed that MT immunostaining was significantly lower in advanced gastric carcinoma cases, along
with a higher percentage of MT immunostaining observed in gastric mucosa adjacent to the tumors as compared to the cancer tissues (Tuccari et al., 2000).
Similarly, Jansen et al. observed that gastric carcinomas,
colorectal adenomas, and carcinomas had significantly
lower MT-expression as determined by radioimmunoassay
than that of corresponding normal-appearing tissues
(Janssen et al., 2000). However, using differential display
mRNA analysis, Ebert et al. demonstrated overexpression
of MT-2A by Northern blot analysis and observed overexpression of MT by immunohistochemistry in tissues
obtained from gastric carcinoma (Ebert et al., 2000).
Amongst others, Pedersen et al. (2009) have attributed
variations observed in MT expression to lack of standardization in the collection of tumors with regard to variability of the tumor stages and MT staining pattern (such as
nuclear or cytoplasmic) used in the experimental protocol.
The current thinking is that GISTs, which are tumors
of mesodermal origin, are derived from the interstitial
cells of Cajal (ICC) since the majority of GISTs express
CD117 which is similar to that observed in ICCs (Kindblom et al., 1998; Min, 2010). The ICCs were first
described by Santiago Ramon y Cajal (1893) and have
been regarded as pacemaker cells of the gastrointestinal
tract (Thuneberg, 1982). Recently, Min (2010) has suggested from ultrastructural observations that GISTs
develop from gut stem cells, which could differentiate further to ICC or muscle cells under the control of c-KIT
(Torihashi et al., 1999). On the other hand, gastric carcinomas are epithelial tumors of endodermal origin. Differential MT expression in GISTs and gastric carcinoma
could, therefore, be due to the histogenesis of the tumors.
Moreover, MT isoforms are known to be expressed in a
tissue specific pattern and believed to play distinct roles
in different types of cancer cells (Cherian et al., 2003).
In summary, we have demonstrated that MT-2A mRNA
expression and MT protein expression as detected by
272
SOO ET AL.
immunohistochemistry were significantly lower in GIST
compared with gastric carcinoma. It would appear that
nuclear expression of MT may reflect an underlying pathobiology of GIST that is distinct from gastric carcinoma.
ACKNOWLEDGMENTS
The authors thank Dr. Aye Aye Thike from the
Department of Pathology, Singapore General Hospital
for her assistance in the immunoscoring process, Dr.
Manuel Salto-Telez from the Department of Pathology,
National University Hospital for facilitating the GIST
and gastric cancer TMAs used in this study, and Ms Bay
Song Lin for technical assistance.
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expressions, carcinoma, metallothionein, gastrointestinal, differential, gastric, tumors, stroma
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